Epigenetic mechanisms of age-dependent KIR2DL4 expression in T cells

Abstract: Killer Ig-like receptor (KIR) expres-sion is mostly restricted to NK cells controlling their activation. With increasing age, KIRs are ex-pressed on T cells and contribute to age-related diseases. We examined epigenetic mechanisms that determine the competency of T cells to transcribe KIR2DL4. Compared with Jurkat cells and CD4CD28 T cells from young individuals, DNA methyltransferase (DNMT) inhibition was strikingly more effective in T cells from elderly adults and the CD4CD28 – T cell line HUT78 to induce KIR2DL4 transcription. In these susceptible cells, the KIR2DL4 promoter was partially demethyl-ated, and dimethylated H3-Lys 4 was increased, and all other histone modifications were character-istic for an inactive promoter. In comparison, NK cells had a fully demethylated KIR2DL4 promoter and the full spectrum of histone modifications in-dicative of active transcription with H3 and H4 acetylation, di- and trimethylated H3-Lys 4, and reduced, dimethylated H3-Lys 9. These results suggest that an increased competency of T cells to express KIR2DL4 with aging is conferred by a selective increase in H3-Lys 4 dimethylation and limited DNA demethylation. The partially accessi-ble promoter is sensitive to DNMT inhibition, which is sufficient to induce full transcription with-out further histone acetylation and methylation. J. Leukoc. Biol. 84: 000–000; 2008. Key Words: molecular biology of aging deacetylase cellular immunology cellular senescence gene expressio